Niraparib Approved in Europe for Ovarian Cancer

Mansoor Raza Mirza, MD

The European Commission has approved niraparib (Zejula) as a maintenance therapy for women with platinum-sensitive relapsed high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy.

Niraparib is indicated regardless of a patient’s BRCA mutation status, making it the only once-daily PARP 1/2 inhibitor approved in Europe that does not require biomarker testing, Tesaro, the manufacturer of the treatment, noted in a press release.

The FDA approved niraparib for this indication in March, and both regulatory agencies relied on results from the double-blind, phase III, placebo-controlled, international ENGOT-OV16/NOVA trial of 553 women. Investigators found that niraparib reduced the risk for disease progression or death by 73% in patients with germline BRCA mutations (hazard ratio [HR], 0.27) and by 55% in patients without germline BRCA mutations (HR, 0.45).^1,2

“[The] approval of Zejula is an exciting step forward for the ovarian cancer community in Europe. While platinum-based chemotherapy has proven to be effective, its efficacy unfortunately diminishes over time, and progression-free survival becomes shorter after each successive platinum treatment,” Mansoor Raza Mirza, MD, ENGOT-OV16/NOVA study chair and chief oncologist at Rigshospitalet, Copenhagen, said in a press release. “Zejula now provides an opportunity to increase progression-free survival after platinum therapy, and will have a profound impact for women and their families.”

The median progression-free survival (PFS) with maintenance niraparib in the NOVA trial was 21 months compared with 5.5 months for placebo in patients with germline BRCA mutations (HR, 0.26; 95% CI, 0.17-0.41; P <.0001). These findings remained consistent across subgroups of patients, including those without BRCA mutations.

The study randomly assigned patients to 1 of 2 independent cohorts. In the first, 201 patients with germline BRCA mutations received 300 mg niraparib daily (n = 138) or placebo (n = 65). In the second cohort, 345 patients with non-germline BRCA-mutant tumors received the PARP Inhibitor (n = 231) or placebo (n = 114). Patients in this group were tested for homologous recombination deficiency (HRD), and could be either positive (n = 162) or negative (n = 134). Of those who tested positive, 47 had somatic BRCA mutations and 115 were wild-type.

Across both cohorts, the majority of patients had stage III cancer (68.8% to 74.1%). Approximately half of patients had achieved a complete response to prior platinum-based therapy and a quarter had received prior bevacizumab. In the non-BRCA-mutant arm, 33.8% and 32.8% of patients had received ≥3 prior therapies.

In the germline BRCA mutation group, the chemotherapy-free interval was 22.8 months with niraparib compared with 9.4 months for placebo (HR, 0.26; 95% CI, 0.17-0.41; P <.001). The median time to subsequent therapy was 21 months with niraparib versus 8.4 months with placebo (HR, 0.31; 95% CI, 0.21-0.48).

The median time to progression or death during the first subsequent therapy following the study (PFS2) was 25.8 months for those who received maintenance niraparib versus 19.5 months for placebo (HR, 0.48; 95% CI, 0.28-0.82; P = .006).

Findings for overall survival were not yet mature (fewer than 20% of events). At the time of the analysis, niraparib had reduced the risk of death by 27% versus placebo, although this finding was not statistically significant (HR, 0.73; 95% CI, 0.480-1.125; P = .1545).

In patients with HRD-positive, BRCA wild-type tumors, median PFS was 9.3 versus 3.7 months for niraparib and placebo, respectively (HR, 0.38; 95% CI, 0.23-0.63; P <.001). In those with HRD-positive, somatic BRCA-mutated tumors, the median PFS was 20.9 months with niraparib versus 11.0 months for placebo (HR, 0.27; 95% CI, 0.08-0.90; P = .02). In patients with HRD-negative, non-germline BRCA-mutated tumors, median PFS was 6.9 versus 3.8 months for niraparib and placebo, respectively (HR, 0.58; 95% CI, 0.36-0.92; P = .02).

In those with non-germline BRCA mutations regardless of HRD status, the median chemotherapy-free interval was 12.7 versus 8.6 months for niraparib and placebo, respectively (HR, 0.50; 95% CI, 0.37-0.67; P <.001). The median time to subsequent therapy was 11.8 versus 7.2 months (HR, 0.55; 95% CI, 0.41-0.72; P <.001) and the median PFS2 was 18.6 and 15.6 months for the niraparib and placebo arms, respectively (HR, 0.69; 95% CI, 0.49-0.96; P = .03).

Across cohorts, 14.7% of 367 niraparib-treated patients discontinued therapy due to an adverse event (AE) compared with 2.2% of the 179 patients in the placebo arm. There were no treatment-related deaths in the study. In the follow-up period, 1 patient in the niraparib arm and 2 in the placebo group died of myelodysplastic syndrome or acute myeloid leukemia. One of these deaths in each arm was deemed to be treatment related.

The most common all-grade AEs for niraparib versus placebo, respectively, were nausea (73.6% vs 35.2%, respectively), thrombocytopenia (61.3% vs 5.6%), fatigue (59.4% vs 41.3%), anemia (50.1% vs 6.7%), constipation (39.8% vs 20.1%), vomiting (34.3% vs 16.2%), and neutropenia (30.2% vs 6.1%).

The most common grade 3/4 AEs in the niraparib arm were hematologic, and included thrombocytopenia (33.8%), anemia (25.3%), and neutropenia (19.6%). The most common non-hematologic AEs were hypertension (8.2%), fatigue (8.2%), and nausea (3%). A majority of hematologic AEs were experienced in the first 3 cycles.

“With the introduction of Zejula, treatment of women with recurrent ovarian cancer will improve markedly,” Andreas Du Bois, MD, PhD, center director of Gynecology & Gynecologic Oncology, Kliniken Essen-Mitte, said in a press release. “Patients and their physicians are now empowered with an additional option to utilize after a response to chemotherapy, regardless of BRCA mutation status, where the previous alternative for most was a period of watching and waiting instead of actively controlling their disease.” Mutliple References:

References

1. Mirza MR, Monk BJ, Oza A, et al. A randomized, double-blind phase 3 trial of maintenance therapy with niraparib vs placebo in patients with platinum-sensitive recurrent ovarian cancer (ENGOT-OV16/NOVA trial). Presented at: 2016 ESMO Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract LBA3_PR.
2. Mirza MR, Monk B, Herrstedt J, et al. Niraparib maintenance therapy in platinum-sensitive recurrent ovarian cancer [published online October 8, 2016]. N Engl J Med. 10.1056/NEJMoa1611310.